Marc H.A. Bemelmans

Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection

Accelerated recovery from surgery has been achieved when patients are managed within a multimodal Enhanced Recovery After Surgery (ERAS) protocol. This study evaluated the benefit of an ERAS programme for patients undergoing liver resection.

The effect of a multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study

OBJECTIVES This study was conducted to evaluate the added value of an enhanced recovery after surgery (ERAS) programme in laparoscopic liver resections for solid tumours. METHODS Patients undergoing laparoscopic liver resection between July 2005 and July 2008 were included. Indications for resections included presumed benign and malignant liver lesions. Primary outcome was total length of hospital stay (LOS). Secondary outcomes were functional recovery, complications, conversions, blood loss and duration of operation. RESULTS Thirteen patients were treated by laparoscopic liver resections in the ERAS programme in one centre (group 1). Their outcomes were compared with outcomes of 13 laparoscopic procedures performed either before the introduction of the ERAS programme during 2003-2005 in the same centre or during the same period in other centres using traditional care (group 2). Median total LOS was 5.0 days (range 3-10 days) in group 1 and 7.0 days (3-12 days) in group 2. This difference was not statistically significant. Functional recovery occurred 2 days earlier in group 1 (median 3.0 days [range 1-7 days] vs. median 5.0 days [range 2-8 days]; P < 0.044). There were no significant differences in complications, conversions or duration of operation. Blood loss was significantly less in the ERAS group (median 50 ml [range 50-200 ml] vs. median 250 ml [range 50-800 ml]; P < 0.002). CONCLUSIONS This exploratory, multicentre, fast-track laparoscopic liver resection study is the first such study conducted. Although small, the study suggests that a multimodal enhanced recovery programme in laparoscopic liver surgery is feasible, safe and may lead to accelerated functional recovery and reductions in LOS.

Open versus laparoscopic left lateral hepatic sectionectomy within an enhanced recovery ERAS® programme (ORANGE II – Trial): study protocol for a randomised controlled trial

BackgroundThe use of lLaparoscopic liver resection in terms of time to functional recovery, length of hospital stay (LOS), long-term abdominal wall hernias, costs and quality of life (QOL) has never been studied in a randomised controlled trial. Therefore, this is the subject of the international multicentre randomised controlled ORANGE II trial.MethodsPatients eligible for left lateral sectionectomy (LLS) of the liver will be recruited and randomised at the outpatient clinic. All randomised patients will undergo surgery in the setting of an ERAS programme. The experimental design produces two randomised arms (open and laparoscopic LLS) and a prospective registry. The prospective registry will be based on patients that cannot be randomised because of the explicit treatment preference of the patient or surgeon, or because of ineligibility (not meeting the in- and exclusion criteria) for randomisation in this trial. Therefore, all non-randomised patients undergoing LLS will be approached to participate in the prospective registry, thereby allowing acquisition of an uninterrupted prospective series of patients. The primary endpoint of the ORANGE II trial is time to functional recovery. Secondary endpoints are postoperative LOS, percentage readmission, (liver-specific) morbidity, QOL, body image and cosmetic result, hospital and societal costs over 1 year, and long-term incidence of incisional hernias. It will be assumed that in patients undergoing laparoscopic LLS, length of hospital stay can be reduced by two days. A sample size of 55 patients in each randomisation arm has been calculated to detect a 2-day reduction in LOS (90% power and α = 0.05 (two-tailed)).The ORANGE II trial is a multicenter randomised controlled trial that will provide evidence on the merits of laparoscopic surgery in patients undergoing LLS within an enhanced recovery ERAS programme.Trial registrationClinicalTrials.gov NCT00874224.

The liver-first approach for synchronous colorectal liver metastasis: a 5-year single-centre experience

BACKGROUND For patients who present with synchronous colorectal carcinoma and colorectal liver metastasis (CRLM), a reversed treatment sequence in which the CRLM are resected before the primary carcinoma has been proposed (liver-first approach). The aim of the present study was to assess the feasibility and outcome of this approach for synchronous CRLM. METHODS Between 2005 and 2010, 22 patients were planned to undergo the liver-first approach. Feasibility and outcomes were prospectively evaluated. RESULTS Of the 22 patients planned to undergo the liver-first strategy, the approach was completed in 18 patients (81.8%). The main reason for treatment failure was disease progression. Patients who completed treatment and patients who deviated from the protocol had a similar location of the primary tumour, as well as comparable size, number and distribution of CRLM (all P > 0.05). Post-operative morbidity and mortality were 27.3% and 0% following liver resection and 44.4% and 5.6% after colorectal surgery, respectively. On an intention-to-treat-basis, overall 3-year survival was 41.1%. However, 37.5% of patients who completed the treatment had developed recurrent disease at the time of the last follow-up. CONCLUSIONS The liver-first approach is feasible in approximately four-fifths of patients and can be performed with peri-operative mortality and morbidity similar to the traditional treatment paradigm. Patients treated with this novel strategy derive a considerable overall-survival-benefit, although disease-recurrence-rates remain relatively high, necessitating a multidisciplinary approach.

Sarcopenia negatively affects preoperative total functional liver volume in patients undergoing liver resection.

OBJECTIVES Sarcopenia may negatively affect short-term outcomes after liver resection. The present study aimed to explore whether total functional liver volume (TFLV) is related to sarcopenia in patients undergoing partial liver resection. METHODS Analysis of total liver volume and tumour volume and measurements of muscle surface were performed in patients undergoing liver resection using OsiriX(®) and preoperative computed tomography. The ratio of TFLV to bodyweight was calculated as: [TFLV (ml)/bodyweight (g)]*100%. The L3 muscle index (cm(2) /m(2) ) was then calculated by normalizing muscle areas (at the third lumbar vertebral level) for height. RESULTS Of 40 patients, 27 (67.5%) were classified as sarcopenic. There was a significant correlation between the L3 skeletal muscle index and TFLV (r= 0.64, P < 0.001). Median TFLV was significantly lower in the sarcopenia group than in the non-sarcopenia group [1396 ml (range: 1129-2625 ml) and 1840 ml (range: 867-2404 ml), respectively; P < 0.05]. Median TFLV : bodyweight ratio was significantly lower in the sarcopenia group than in the non-sarcopenia group [2.0% (range: 1.4-2.5%) and 2.3% (range: 1.5-2.5%), respectively; P < 0.05]. CONCLUSIONS Sarcopenic patients had a disproportionally small preoperative TFLV compared with non-sarcopenic patients undergoing liver resection. The preoperative hepatic physiologic reserve may therefore be smaller in sarcopenic patients.

Outcomes of extended versus limited indications for patients undergoing a liver resection for colorectal cancer liver metastases.

BACKGROUND Currently, resection criteria for colorectal cancer liver metastases (CRCLM) are only limited by remnant liver function. Morbidity and survival after a partial hepatectomy with limited or extended indication criteria were compared. METHODS/DESIGN Between 1991 and 2010, patients undergoing a liver resection for CRCLM with limited (n = 169) or extended indication criteria (n = 129) were retrospectively identified in a prospectively collected single-centre database. Limited indication criteria were defined as less than three unilateral, not centrally located liver metastases in the absence of extra hepatic metastases. The extended criteria were only limited by predicted remnant liver volume and patients fitness. Data on co-morbidity, resection margin, short- and long-term morbidity, disease-free (DFS) and overall survival were compared. RESULTS Patients with limited indications had less major complications (19.5% vs. 33.1%, P < 0.01), longer overall survival of 68.8 months [confidence interval (CI) 46.5-91.1] vs. 41.4 months (CI 33.4-49.0, P ≤ 0.001) and longer median DFS of 22.0 months [confidence interval (CI) 15.8-28.2] vs 10.2 months (CI 8.4-11.9, P < 0.001) compared with the extended indication group. Cure rates, defined as 10-year DFS, were 35.5% and 15.8%, respectively. Fewer patients in the extended indication group underwent an R0 resection (92.9% vs. 77.5%, P < 0.001). Only 17% of all R1 resected patients had recurrences at the transection plane. CONCLUSION A partial hepatectomy for CRCLM with extended indications seems justified but is associated with higher complication rates, earlier recurrence and lower overall survival compared with limited indications. However, the median 5-year survival was substantial and a cure was achieved in 15.8% of patients.

Total intermittent Pringle maneuver during liver resection can induce intestinal epithelial cell damage and endotoxemia.

Objectives The intermittent Pringle maneuver (IPM) is frequently applied to minimize blood loss during liver transection. Clamping the hepatoduodenal ligament blocks the hepatic inflow, which leads to a non circulating (hepato)splanchnic outflow. Also, IPM blocks the mesenteric venous drainage (as well as the splenic drainage) with raising pressure in the microvascular network of the intestinal structures. It is unknown whether the IPM is harmful to the gut. The aim was to investigate intestinal epithelial cell damage reflected by circulating intestinal fatty acid binding protein levels (I-FABP) in patients undergoing liver resection with IPM. Methods Patients who underwent liver surgery received total IPM (total-IPM) or selective IPM (sel-IPM). A selective IPM was performed by selectively clamping the right portal pedicle. Patients without IPM served as controls (no-IPM). Arterial blood samples were taken immediately after incision, ischemia and reperfusion of the liver, transection, 8 hours after start of surgery and on the first post-operative day. Results 24 patients (13 males) were included. 7 patients received cycles of 15 minutes and 5 patients received cycles of 30 minutes of hepatic inflow occlusion. 6 patients received cycles of 15 minutes selective hepatic occlusion and 6 patients underwent surgery without inflow occlusion. Application of total-IPM resulted in a significant increase in I-FABP 8 hours after start of surgery compared to baseline (p<0.005). In the no-IPM group and sel-IPM group no significant increase in I-FABP at any time point compared to baseline was observed. Conclusion Total-IPM in patients undergoing liver resection is associated with a substantial increase in arterial I-FABP, pointing to intestinal epithelial injury during liver surgery. Trial Registration ClinicalTrials.gov NCT01099475

Nodular Regenerative Hyperplasia Secondary to Neoadjuvant Chemotherapy for Colorectal Liver Metastases

Liver resection is the only curative treatment for patients with colorectal liver metastases (CLMs). Neoadjuvant chemotherapy can improve resectability but has a potential harmful effect on the nontumorous liver. Patients with chemotherapy-induced hepatic injury undergoing liver surgery have higher risks of post-resectional morbidity. We present two cases of patients without pre-existent liver disease treated with oxaliplatin-based chemotherapy followed by surgical resection of their CLMs. Their intra-operative liver specimen showed morphologic abnormalities characteristic of nodular regenerative hyperplasia (NRH). NRH led to portal hypertension in both patients that resulted in deleterious post-resectional complications and death of one patient. Interestingly, the other patient underwent two repeat nonanatomic liver resections because of recurrent CLMs. The intra-operative liver specimen still showed signs of NRH and sinusoidal congestion, but the post-resectional courses were uneventful. Nevertheless, caution is recommended in patients with suspected NRH. Careful volumetric analysis should guide the operative strategy. When future remnant liver volume is regarded insufficient, portal vein embolization or restrictive surgery should be considered.

Mechanism of induction of tolerance to tumour necrosis factor (TNF): no involvement of modulators of TNF bioavailability or receptor binding.

The repetitive administration of low doses of hTNF to mice induces tolerance to the lethal effects of mTNF. The underlying mechanism is unknown. In this study we have investigated whether changes in bioavailability and receptor binding could account for the observed differences. To that end we compared the pharmacokinetics of mTNF, the antibody response to TNF, the levels of soluble TNF receptors and the receptor binding of TNF in tolerant and control mice. No differences in pharmacokinetic parameters were observed. An antibody response towards hTNF occurred but the antibodies did not neutralize the mTNF used as a challenge. Furthermore, tolerance failed to protect mice against lethality induced by TNF in the presence of galactosamine, where 100- to 1000-fold lower dose of TNF is required. Also, tolerance could be induced in athymic nude mice where the antibody response is absent. These results show that the mechanism of induction of tolerance is not due to an antibody response. No differences in levels of soluble receptors or receptor binding could be observed in tolerant vs control mice. We conclude that the induction of tolerance involves mechanisms operating at the post-receptor pathways.

A survey in the hepatopancreatobiliary community on ways to enhance patient recovery.

OBJECTIVES Both laparoscopic techniques and multimodal enhanced recovery programmes have been shown to improve recovery and reduce length of hospital stay. Interestingly, evidence-based care programmes are not widely implemented, whereas new, minimally invasive surgical procedures are often adopted with very little evidence to support their effectiveness. The present survey aimed to shed light on experiences of the adoption of both methods of optimizing recovery. METHODS An international, web-based, 18-question, electronic survey was composed in 2010. The survey was sent out to 673 hepatopancreatobiliary (HPB) centres worldwide in June 2010 to investigate international experiences with laparoscopic liver surgery, fast-track recovery programmes and surgery-related equipoise in open and laparoscopic techniques and to assess opinions on strategies for adopting laparoscopic liver surgery in HPB surgical practice. RESULTS A total of 507 centres responded (response rate: 75.3%), 161 of which finished the survey completely. All units reported performing open liver resections, 24.2% performed open living donor resections, 39.1% carried out orthotopic liver transplantations, 87.6% had experience with laparoscopic resections and 2.5% performed laparoscopic living donor resections. A median of 50 (range: 2-560) open and 9.5 (range: 1-80) laparoscopic liver resections per surgical unit were performed in 2009. Patients stayed in hospital for a median of 7 days (range: 2-15 days) after uncomplicated open liver resection and a median of 4 days (range: 1-10 days) after uncomplicated laparoscopic liver resection. Only 28.0% of centres reported having experience with fast-track programmes in liver surgery. The majority considered the instigation of a randomized controlled trial or a prospective register comparing the outcomes of open and laparoscopic techniques to be necessary. CONCLUSIONS Worldwide dissemination of laparoscopic liver resection is substantial, although laparoscopic volumes are low in the majority of HPB centres. The adoption of enhanced recovery programmes in liver surgery is limited and should be given greater attention.